The interaction of macrophages with lymphocytes is a prerequisite for antigen-induced stimulation of in vitro lymphocyte proliferation and the production of a variety of mediators such as osteoclast activation factor (OAF) which results in bone resorption. This principle was tested to determine the nature of the OAF producing cells. OAF was found to be produced by lymphocytes, provided macrophages were there to activate them to make it. Furthermore, "OAF-like" activity was also found in the supernatants of long-term "B" lymphoid cell lines. We have therefore also studied which class of lymphocytes (B or T) macrophages interact with. Macrophages were found to restore the response of purified T but not B lymphocytes, whereas the reaction of both T and B lymphocytes was enhanced in lymphocyte suspensions containing both B and T cells. Therefore, macrophages appear to facilitate the cooperation of T and B cells, but do so by interacting only with T cells. The differences in interaction of T and B receptors with stimulants suggested by these findings are being studied further.